Compounds useful for inhibition of farnesyl protein transferase

ABSTRACT

Novel compounds of the formula:  
                 
 
     or a pharmaceutically acceptable salt or solvate thereof, wherein:  
     a represents N or NO − ;  
     R 1  and R 3  are the same or different and each represents halo;  
     R 2  and R 4  are the same or different and each is selected from H and halo, provided that at least one of R 2  and R 4  is H;  
     T is a substituent selected from SO 2 R or  
                 
 
     Z is O or S;  
     n is zero or an integer from 1 to 6;  
     R is alkyl aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl, heterocycloalkyl, or N(R 5 ) 2 ;  
     R 5  is H, alkyl, aryl, heteroaryl or cycloalkyl.  
     Also disclosed are methods of inhibiting farnesyl protein transferase and methods for treating tumor cells.

BACKGROUND

[0001] WO 95/10516, published Apr. 20, 1995 discloses tricycliccompounds useful for inhibiting farnesyl protein transferase.

[0002] In view of the current interest in inhibitors of farnesyl proteintransferase, a welcome contribution to the art would be compounds usefulfor the inhibition of farnesyl protein transferase. Such a contributionis provided by this invention.

SUMMARY OF THE INVENTION

[0003] This invention provides compounds useful for the inhibition offarnesyl protein transferase (FPT). The compounds of this invention arerepresented by the formula:

[0004] or a pharmaceutically acceptable salt or solvate thereof,wherein:

[0005] a represents N or NO⁻;

[0006] R¹ and R³ are the same or different and each represents halo;

[0007] R² and R⁴ are the same or different and each is selected from Hand halo, provided that at least one of R² and R⁴ is H;

[0008] T is a substituent selected from SO₂R or

[0009] Z is O or S;

[0010] n is zero or an integer from 1 to 6;

[0011] R is alkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl,cycloalkyl, heterocycloalkyl, or N(R⁵)₂;

[0012] R⁵ is H, alkyl, aryl, heteroaryl or cycloalkyl.

[0013] The compounds of this invention: (i) potently inhibit farnesylprotein transferase, but not geranylgeranyl protein transferase I, invitro; (ii) block the phenotypic change induced by a form oftransforming Ras which is a farnesyl acceptor but not by a form oftransforming Ras engineered to be a geranylgeranyl acceptor; (iii) blockintracellular processing of Ras which is a farnesyl acceptor but not ofRas engineered to be a geranylgeranyl acceptor; and (iv) block abnormalcell growth in culture induced by transforming Ras.

[0014] The compounds of this invention inhibit farnesyl proteintransferase and the farnesylation of the oncogene protein Ras. Thus,this invention further provides a method of inhibiting farnesyl proteintransferase, (e.g., ras farnesyl protein transferase) in mammals,especially humans, by the administration of an effective amount of thecompounds of formula 1.0. The administration of the compounds of thisinvention to patients, to inhibit farnesyl protein transferase is usefulin the treatment of the cancers described below.

[0015] This invention provides a method for inhibiting or treating theabnormal growth of cells, including transformed cells, by administeringan effective amount of a compound of this invention. Abnormal growth ofcells refers to cell growth independent of normal regulator mechanisms(e.g., loss of contact inhibition). This includes the abnormal growthof: (1) tumor cells (tumors) expressing an activated Ras oncogene; (2)tumor cells in which the Ras protein is activated as a result ofoncogenic mutation in another gene: and (3) benign and malignant cellsof other proliferative diseases in which aberrant Ras activation occurs.

[0016] This invention also provides a method for inhibiting or treatingtumor growth by administering an effective amount of the tricycliccompounds, described herein, to a mammal (e.g., a human) in need of suchtreatment. In particular, this invention provides a method forinhibiting or treating the growth of tumors expressing an activated Rasoncogene by the administration of an effective amount of the compoundsof formula 1.0. Examples of tumors which may be inhibited or treatedinclude, but are not limited to, lung cancer (e.g., lungadenocarcinoma), pancreatic cancers (e.g., pancreatic carcinoma such as,for example, exocrine pancreatic carcinoma), colon cancers (e.g.,colorectal carcinomas, such as, for example, colon adenocarcinoma andcolon adenoma), myeloid leukemias (for example, acute myelogenousleukemia (AML)), thyroid follicular cancer, myelodysplastic syndrome(MDS), bladder carcinoma, epidermal carcinoma, breast cancer andprostate cancer.

[0017] It is believed that this invention also provides a method forinhibiting or treating proliferative diseases, both benign andmalignant, wherein Ras proteins are aberrantly activated as a result ofoncogenic mutation in other genes—i.e., the Ras gene itself is notactivated by mutation to an oncogenic form—with said inhibition ortreatment being accomplished by the administration of an effectiveamount of a compound of formula 1.0 to a mammal (e.g., a human) in needof such treatment. For example, the benign proliferative disorderneurofibromatosis, or tumors in which Ras is activated due to mutationor overexpression of tyrosine kinase oncogenes (e.g., neu, src, abl,lck, and fyn), may be inhibited or treated by the tricyclic compoundsdescribed herein.

[0018] The compounds of formula 1.0 useful in the methods of thisinvention inhibit or treat the abnormal growth of cells. Without wishingto be bound by theory it is believed that these compounds may functionthrough the inhibition of G-protein function, such as ras p21, byblocking G-protein isoprenylation, thus making them useful in thetreatment of proliferative diseases such as tumor growth and cancer.Without wishing to be bound by theory, it is believed that thesecompounds inhibit ras farnesyl protein transferase, and thus showantiproliferative activity against ras transformed cells.

DETAILED DESCRIPTION OF THE INVENTION

[0019] As used herein, the following terms are used as defined belowunless otherwise indicated:

[0020] MH⁺—represents the molecular ion plus hydrogen of the molecule inthe mass spectrum;

[0021] Et (or ET)—represents ethyl (C₂H₅);

[0022] alkyl—represents straight and branched carbon chains that containfrom one to twenty carbon atoms, preferably one to six carbon atoms;

[0023] halo—represents fluoro, chloro, bromo and iodo;

[0024] cycloalkyl—represents saturated carbocyclic rings branched orunbranched of from 3 to 20 carbon atoms, preferably 3 to 7 carbon atoms;

[0025] heterocycloalkyl—represents a saturated, branched or unbranchedcarbocylic ring containing from 3 to 15 carbon atoms, preferably from 4to 6 carbon atoms, which carbocyclic ring is interrupted by 1 to 3hetero groups selected from —O—, —S— or —NR⁹— (wherein R⁹ can be, forexample, —C(O)N(R¹⁰)₂, —CH₂C(O)N(R¹⁰)₂, —SO₂R¹⁰, —SO₂N(R¹⁰)₂, —C(O)R¹¹,—C(O)—O—R¹¹, alky, aryl, aralkyl, cycloalkyl, heterocycloalkyl orheteroaryl; each R¹⁰ independently represents H, alkyl, aryl, or aralkyl(e.g., benzyl); and R¹¹ is alkyl, aryl, aralkyl, heteroaryl orheterocycloalkyl)—(suitable heterocycloalkyl groups include 2- or3-tetrahydrofuranyl, 2- or 3-tetrahydrothienyl, 2-, 3- or 4-piperidinyl,2- or 3-pyrrolidinyl, 2- or 3-piperizinyl, 2- or 4-dioxanyl, etc.—withpreferred heterocycloalkyl groups being 2- , 3- or 4-piperidinylsubstituted with R¹⁰ on the piperidinyl nitrogen);

[0026] aryl (including the alkyl portion of aryloxy andaralkyl)—represents a carbocyclic group containing from 6 to 15 carbonatoms and having at least one aromatic ring (e.g., aryl is a phenylring), with all available substitutable carbon atoms of the carbocyclicgroup being intended as possible points of attachment, said carbocyclicgroup being optionally substituted (e.g., 1 to 3) with one or more ofhalo, alkyl, hydroxy, alkoxy, phenoxy, CF₃, amino, alkylamino,dialkylamino. —COOR¹¹ or —NO₂ (wherein R¹¹ is H, alkyl, aryl, heteroarylor cycloalkyl); and

[0027] heteroaryl—represents cyclic groups, optionally substituted withR³ and R⁴, having at least one heteroatom selected from O, S or N, saidheteroatom interrupting a carbocyclic ring structure and having asufficient number of delocalized pi electrons to provide aromaticcharacter, with the aromatic heterocyclic groups preferably containingfrom 2 to 14 carbon atoms, e.g., triazolyl, 2-, 3- or 4-pyridyl orpyridyl N-oxide (optionally substituted with R¹¹ as defined above),wherein pyridyl N-oxide can be represented as:

[0028] The following solvents and reagents are referred to herein by theabbreviations indicated: ethanol (EtOH); methanol (MeOH)); acetic acid(HOAc or AcOH); ethyl acetate (EtOAc); N,N-dimethyl-formamide (DMF);trifluoroacetic acid (TFA); trifluoro-acetic anhydride (TFAA);1-hydroxybenzotriazole (HOBT); 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (DEC); diisobutylaluminum hydride(DIBAL); and4-methylmorpholine (NMM).

[0029] The positions in the tricyclic ring system are:

[0030] Those skilled in the art will also appreciate that the S and Rstereochemistry for the C-11 position of the tricyclic ring is asfollows:

[0031] Preferred halo atoms for R¹, R², R³, and R⁴ in formula 1.0 areselected from: Br, Cl or I, with Br and Cl being preferred.

[0032] Compounds of formula 1.0 include compounds of the formula:

[0033] wherein R¹ and R³ are the same or different halo and a and T areas defined above. Preferably, for these dihalo compounds, R¹ and R³ areindependently selected from Br or Cl, and more preferably R¹ is Br andR³ is Cl.

[0034] Compounds of formula 1.0 include compounds of formulas 1.1 and1.2:

[0035] wherein R¹, R³ and R⁴ in formula 1.1 are halo, and R¹, R² and R³in formula 1.2 are halo. Compounds of formula 1.1 are preferred.

[0036] Preferably, in formula 1.1. R¹ is Br, R³ is Cl, and R⁴ is halo.More preferably, in formula 1.1. R¹ is Br, R³ is Cl, and R⁴ is Br.

[0037] Preferably, in formula 1.2. R¹ is Br, R² is halo, and R³ is Cl.More preferably, in formula 1.1. R¹ is Br, R² is Br, and R³ is Cl.

[0038] Also, preferably, for the compounds of this invention,substituent a in Ring I represents N.

[0039] T is preferably —SO₂methyl or a group

[0040] wherein R is a 3-pydinyl N-oxide, 4-pyridinyl N-oxide,4-piperdinyl, 3-piperdinyl or 3-pyrrolidinyl group, wherein the4-piperdinyl, 3-piperdinyl or 3-pyrrolidinyl groups may be substitutedon the piperindinyl or pyrrolidinyl nitrogen with a group R⁹ which canbe, for example, —C(O)N(R¹⁰)₂, —CHC(O)N(R¹⁰)₂, —SO₂R¹⁰,

[0041] —SO₂N(R¹⁰)₂, —C(O)R¹¹, —C(O)OR¹¹, alkyl, aryl, aralkyl,cycloalkyl, heterocycloalkyl or heteroaryl; each R¹⁰ independentlyrepresents H, alkyl, aryl, or aralkyl (e.g., benzyl); and R¹¹ is alkyl,aryl, aralkyl, heteroaryl or heterocycloalkyl.

[0042] Those skilled in the art will appreciate that compounds offormula 1.0 include compounds of formulas 1.3 and 1.4:

[0043] with compounds of 1.3 being preferred for compounds of formula1.1, and with compounds of Formula 1.4 being preferred for compounds offormula 1.2.

[0044] Thus, compounds of the invention include compounds of theformulas:

[0045] Certain compounds of the invention may exist in differentisomeric (e.g., enantiomers and diastereoisomers) forms. The inventioncontemplates all such isomers both in pure form and in admixture,including racemic mixtures. Enol forms are also included.

[0046] Certain compounds of formula 1.0 will be acidic in nature. e.g.those compounds which possess a carboxyl or phenolic hydroxyl group.These compounds may form pharmaceutically acceptable salts. Examples ofsuch salts may include sodium, potassium, calcium, aluminum, gold andsilver salts. Also contemplated are salts formed with pharmaceuticallyacceptable amines such as ammonia, alkyl amines, hydroxyalkylamines.N-methylglucamine and the like.

[0047] Certain basic compounds of formula 1.0 also form pharmaceuticallyacceptable salts, e.g., acid addition salts. For example, thepyrido-nitrogen atoms may form salts with strong acid, while compoundshaving basic substituents such as amino groups also form salts withweaker acids. Examples of suitable acids for salt formation arehydrochloric, sulfuric, phosphoric, acetic, citric, oxalic, malonic,salicylic, malic, fumaric, succinic, ascorbic, maleic, methane-sulfonicand other mineral and carboxylic acids well known to those in the art.The salts are prepared by contacting the free base form with asufficient amount of the desired acid to produce a salt in theconventional manner. The free base forms may be regenerated by treatingthe salt with a suitable dilute aqueous base solution such as diluteaqueous NaOH, potassium carbonate, ammonia and sodium bicarbonate. Thefree base forms differ from their respective salt forms somewhat incertain physical properties such as solubility in polar solvents, butthe acid and base salts are otherwise equivalent to their respectivefree base forms for purposes of the invention.

[0048] All such acid and base salts are intended to be pharmaceuticallyacceptable salts within the scope of the invention and all acid and basesalts are considered equivalent to the free forms of the correspondingcompounds for purposes of the invention.

[0049] Intermediates useful in the preparation of the compounds of theinvention may be prepared according to the procedures described in WO95/10516 published Apr. 20. 1995. in WO 96/30363 published Oct. 3, 1996.in U.S. Pat. No. 5,151,423 and by the methods described below.

[0050] Compounds of the invention can be prepared according to thereaction:

[0051] In the reaction, the carboxylic acid (14.0) is coupled to thetricyclic amine (13.0) using amide bond forming conditions well known tothose skilled in the art. The substituents are as defined for Formula1.0. For example, carbodiimide coupling methods (e.g., DEC) can be used.For example, the carboxylic acid (14.0) can be reacted With thetricyclic amine (13.0) using DEC/HOBT/NMM in DMF at about 25° C. for asufficient period of time, e.g., about 18 hours, to produce a compoundof Formula 1.0.

[0052] When T is SO₂R, X is halo, preferably, chloro.

[0053] The tricyclic piperadine compound is dissolved in an appropriatesolvent such as DMF of THF. A base is added such as triethylamine, andthe appropriate alkylsulfonylchloride, prepared by methods known in theart, is added to the reaction mixture at 0° C. to ambient temperaturewith stirring. After 1-24 hours, the reaction mixture is added to waterand the product extracted with a suitable solvent such as ethylacetate.The crude reaction product can then be chromatographed on a silica gelcolumn.

[0054] Alkylaminosulfonamido derivatives can be prepared similarly:

[0055] wherein the R⁵groups may be the same or different and each is asdefined above. In this reaction, the tricyclic piperadine compound isdissolved in an appropriate solvent such as DMF of THF. A base is addedsuch as triethylamine, and the appropriate alkylaminosulfonylchloride,prepared by methods known in the art, is added to the reaction mixtureat 0° C. to ambient temperature with stirring. After 1-24 hours, thereaction mixture is added to water and the product extracted with asuitable solvent such as ethylacetate. The crude reaction product canthen be chromatographed on a silica gel column.

[0056] The carboxylic acids (14.0) and the sulfonates (14.2) aregenerally known in the art or can be prepared by methods well known inthe literature.

[0057] Compounds of Formula 13.0 can be prepared from compounds offormula 13.0a:

[0058] wherein R⁶ is H, alkyl, carboalkoxy or any other group that canbe converted into a group T. The compounds of formula 13.0a are preparedby methods known in the art, for example, by methods disclosed in WO95/10516, in WO 96/30363 published Oct. 3, 1996, in U.S. Pat. No.5,151,423 and those described below.

[0059] The double bond in the compounds of formula 13.0a can be cleavedby oxidation, e.g., by the method in Preparative Example 3 below, togive the ketones of formula 15.0 below:

[0060] Compounds of Formula 13.0a wherein the C-3 position of thepyridine ring in the tricyclic structure is substituted by bromo (i.e.,R¹ is Br) can also be prepared by a procedure comprising the followingsteps:

[0061] (a) reacting an amide of the formula

[0062] wherein R^(5a) is hydrogen and R^(6a) is C₁-C₆ alkyl, aryl orheteroaryl; R^(5a) is C₁-C₆ alkyl, aryl or heteroaryl and R^(6a) ishydrogen; R^(5a) and R^(6a) are independently selected from the groupconsisting of C₁-C₆ alkyl and aryl; or R^(5a) and R^(6a), together withthe nitrogen to which they are attached, form a ring comprising 4 to 6carbon atoms or comprising 3 to 5 carbon atoms and one hetero moietyselected from the group consisting of —O— and —NR^(9a)—, wherein R^(9a)is H, C₁-C₆ alkyl or phenyl;

[0063] with a compound of the formula

[0064] wherein R², R³, and R⁴ are as defined above and R^(7a) is Cl orBr, in the presence of a strong base to obtain a compound of the formula

[0065] (b) reacting a compound of step (a) with POCl₃ to obtain a cyanocompound of the formula

[0066] (c) reacting the cyano compound with a piperidine derivative ofthe formula

[0067] wherein L is halo selected from the group consisting of Cl andBr, to obtain a ketone of the formula below:

[0068] (d)(i) cyclizing the ketone under acid conditions (e.g., aluminumchloride, triflic acid, or sulfuric acid) to obtain a compound ofFormula 13.0a wherein R⁶ is methyl, which can be cleaved to give thecompound of formula 15.0.

[0069] Methods for preparing compounds of Formula 13.0a disclosed in WO95/10516, in WO 96/30363 published Oct. 3, 1996, in U.S. Pat. No.5,151,423 and described below employ a tricyclic ketone intermediate.Such intermediates of the formula

[0070] wherein R¹, R², R³ and R⁴ are as defined above, can be preparedby the following process comprising:

[0071] (a) reacting a compound of the formula

[0072]  (i) with an amine of the formula NHR^(5a)R^(6a), wherein R^(5a)and R^(6a) are as defined in the process above; in the presence of apalladium catalyst and carbon monoxide to obtain an amide of theformula:

[0073]  (ii) with an alcohol of the formula R^(10a)OH, wherein R^(10a)is C₁-C₆ lower alkyl or C₃-C₆ cycloalkyl, in the presence of a palladiumcatalyst and carbon monoxide to obtain the ester of the formula

[0074] followed by reacting the ester with an amine of formulaNHR^(5a)R^(6a) to obtain the amide;

[0075] (b) reacting the amide with an iodo-substituted benzyl compoundof the formula

[0076] wherein R², R³, R⁴ and R^(7a) are as defined above in thepresence of a strong base to obtain a compound of the formula

[0077] (c) cyclizing a compound of step (b) with a reagent of theformula R^(8a)MgL, wherein R^(8a) is C₁-C₈ alkyl, aryl or heteroaryl andL is Br or Cl, provided that prior to cyclization, compounds whereinR^(5a) or R^(6a) is hydrogen are reacted with a suitable N-protectinggroup.

[0078] Compounds of Formula 1.0 wherein substituent a is NO (Ring I) canbe made from compounds of Formula 13.0a using procedures well known tothose skilled in the art. For example, the compound of Formula 13.0a canbe reacted with m-chloroperoxybenzoic acid in a suitable organicsolvent, e.g., dichloromethane (usually anhydrous) or methylenechloride, at a suitable temperature, to produce a compound of Formula13.0b

[0079] which can then be cleaved to provide a compound of formula 15.0above.

[0080] Generally, the organic solvent solution of Formula 13.0a iscooled to about 0° C. before the m-chloroperoxybenzoic acid is added.The reaction is then allowed to warm to room temperature during thereaction period. The desired product can be recovered by standardseparation means. For example, the reaction mixture can be washed withan aqueous solution of a suitable base, e.g., saturated sodiumbicarbonate or NaOH (e.g., 1N NaOH), and then dried over anhydrousmagnesium sulfate. The solution containing the product can beconcentrated in vacuo. The product can be purified by standard means,e.g., by chromatography using silica gel (e.g., flash columnchromatography).

[0081] Alternatively, compounds of Formula 1.0, wherein substituent a isNO, can be made from compounds of Formula 1.0. wherein substituent a isN, by the m-chloroperoxybenzoic acid oxidation procedure describedabove.

[0082] Those skilled in the art will appreciate that it is preferable toavoid an excess of m-chloroperoxybenzoic acid when the oxidationreaction is carried out on the compounds of formula 13.0a. In thesereactions an excess of m-chloroperoxybenzoic can cause oxidation of theC-11 double bond.

[0083] Compounds of formula 1.0 wherein Z is S can be prepared fromcompounds of formula 1.0 wherein Z is O by treatment with a suitablesulfur transfer reagent such as Lawsson's reagent.

[0084] Compounds of the invention having asymmetric carbons (e.g.,compounds of the invention wherein X is CH or N have an asymmetriccarbon at the C-11 position of the the tricyclic ring) can be separatedinto enantiomers by techniques known in the art, e.g., by chiral saltresolution or by chiral HPLC.

[0085] Compounds useful in this invention are exemplified by thefollowing examples, which should not be construed to limit the scope ofthe disclosure.

PREPARATIVE EXAMPLE 1

[0086]

[0087]3,10-dibromo-8-chloro-6,11-dihydro-11-one-5H-benzo[5,6]-cycloheptyl-[1,2-b]pyridine(2 gm, 4.98 mmol) was dissolved in 20 ml of dry tetrahydrofuran under adry nitrogen atmosphere. 5 ml of a 1.5 molar solution ofN-methyl-piperidine-4-magnesium chloride was added and the reactionstirred for 18 hours. The reaction mixture was washed with saturatedammonium chloride, dried over magnesium sulfate, filtered and evaporatedto a brown oil which was chromatographed on silica gel using 2.5%methanol/methylene chloride as the eluent to obtain 2.11 gm, 85% of3,10-dibromo-8-chloro-6,11-dihydro-11-(1-methyl-4-piperidinyl)-5H-benzo[5,6]cycloheptyl[1.2-b]pyridin-11-ol.FABMS (M+H)=501

PREPARATIVE EXAMPLE 2

[0088]

[0089] Combine 25.86 g (55.9 mmol) of4-(8-chloro-3-bromo-5,6-dihydro-11H-benzo[5,6]cyclohepta[1.2-b]pyridin-11-ylidene)-1-piperidine-1-carboxylicacid ethyl ester and 250 mL of concentrated H₂SO₄ at −5° C., then add4.8 g (56.4 mmol) of NaNO₃ and stir for 2 hours. Pour the mixture into600 g of ice and basify with concentrated NH₄OH (aqueous). Filter themixture, wash with 300 mL of water, then extract with 500 mL of CH₂Cl₂.Wash the extract with 200 mL of water, dry over MgSO₄, then filter andconcentrate in in vacuo to a residue. Chromatograph the residue (silicagel, 10% EtOAc/CH₂Cl₂) to give 24.4 g (86% yield) of the product.m.p.=165-167° C., Mass Spec.: MH⁺=506 (CI). Elemental analysis:calculated—C, 52.13; H, 4.17; N, 8.29; found—C, 52.18; H, 4.51; N, 8.16.

[0090] Combine 20 g (40.5 mmol) of the product of Step A and 200 mL ofconcentrated H₂SO₄ at 20° C., then cool the mixture to 0° C. Add 7.12 g(24.89 mmol) of 1,3-dibromo-5,5-dimethyl-hydantoin to the mixture andstir for 3 hours at 20° C. Cool to 0° C., add an additional 1.0 g (3.5mmol) of the dibromohydantoin and stir at 20° C. for 2 hours. Pour themixture into 400 g of ice, basify with concentrated NH₄OH (aqueous) at0° C., and collect the resulting solid by filtration. Wash the solidwith 300 mL of water, slurry in 200 mL of acetone and filter to provide19.79 g (85.6% yield) of the product. m.p.=236-237° C., Mass Spec.:MH⁺=584 (CI). Elemental analysis: calculated—C, 45.11; H, 3.44; N, 7.17;found—C, 44.95; H, 3.57; N, 7.16

[0091] Combine 25 g (447 mmol) of Fe filings. 10 g (90 mmol) of CaCl₂and a suspension of 20 g (34.19 mmol) of the product of Step B in 700 mLof 90:10 EtOH/water at 50° C. Heat the mixture at reflux overnight,filter through Celite® and wash the filter cake with 2×200 mL of hotEtOH. Combine the filtrate and washes, and concentrate in vacuo to aresidue. Extract the residue with 600 mL of CH₂Cl₂, wash with 300 mL ofwater and dry over MgSO₄. Filter and concentrate in vacuo to a residue,then chromatograph (silica gel, 30% EtOAc/CH₂Cl₂) to give 11.4 g (60%yield) of the product. m.p.=211-212° C., Mass Spec.: MH⁺=554 (CI).Elemental analysis: calculated—C, 47.55; H, 3.99; N, 7.56; found—C,47.45; H, 4.31; N, 7.49.

[0092] Slowly add (in portions) 20 g (35.9 mmol) of the product of StepC to a solution of 8 g (116 mmol) of NaNO₂ in 120 mL of concentrated HCl(aqueous) at −10° C. Stir the resulting mixture at 0° C. for 2 hours,then slowly add (dropwise) 150 mL (1.44 mole) of 50% H₃PO₂ at 0° C. overa 1 hour period. Stir at 0° C. for 3 hours, then pour into 600 g of iceand basify with concentrated NH₄OH (aqueous). Extract with 2×300 mL ofCH₂Cl₂, dry the extracts over MgSO₄, then filter and concentrate invacuo to a residue. Chromatograph the residue (silica gel, 25%EtOAc/hexanes) to give 13.67 g (70% yield) of the product. m.p.=163-165°C., Mass Spec.: MH⁺=539 (CI). Elemental analysis: calculated—C, 48.97;H, 4.05; N, 5.22; found—C, 48.86; H, 3.91; N, 5.18.

[0093] Combine 6.8 g (12.59 mmol) of the product of Step D and 100 mL ofconcentrated HCl (aqueous) and stir at 85° C. overnight. Cool themixture, pour it into 300 g of ice and basify with concentrated NH₄OH(aqueous). Extract with 2×300 mL of CH₂Cl₂, then dry the extracts overMgSO₄. Filter, concentrate in vacuo to a residue, then chromatograph(silica gel, 10% MeOH/EtOAc+2% NH₄OH (aqueous)) to give 5.4 g (92%yield) of the title compound. m.p.=172-174° C., Mass Spec.: MH⁺=467(FAB). Elemental analysis: calculated—C, 48.69; H, 3.65; N, 5.97;found—C, 48.83; H, 3.80; N, 5.97

PREPARATIVE EXAMPLE 3

[0094]

[0095] Combine 16.6 g (0.03 mole) of the product of Preparative Example3, Step D, with a 3:1 solution of CH₃CN and water (212.65 mL CH₃CN and70.8 mL of water) and stir the resulting slurry overnight at roomtemperature. Add 32.833 g (0.153 mole) of NaIO₄ and then 0.31 g (2.30mmol) of RuO₂ and stir at room temperature give 1.39 g (69% field) ofthe product. (The addition of RuO is accompanied by an exothermicreaction and the temperature climbs from 20° to 30° C.) Stir the mixturefor 1.3 hrs. (temperature returned to 25° C. after about 30 min.), thenfilter to remove the solids and wash the solids with CH₂Cl₂. Concentratethe filtrate in vacuo to a residue and dissolve the residue in CH₂Cl₂.Filter to remove insoluble solids and wash the solids with CH₂Cl₂. Washthe filtrate with water, concentrate to a volume of about 200 mL andwash with bleach, then with water. Extract with 6 N HCl (aqueous). Coolthe aqueous extract to 0° C. and slowly add 50% NaOH (aqueous) to adjustto pH=4 while keeping the temperature <30° C. Extract twice with CH₂Cl₂,dry over MgSO₄ and concentrate in vacuo to a residue. Slurry the residuein 20 mL of EtOH and cool to 0° C. Collect the resulting solids byfiltration and dry the solids in vacuo to give 7.95 g of the product. ¹HNMR (CDCl₃, 200 MHz); 8.7 (s, 1H); 7.85 (m, 6H); 7.5 (d, 2H); 3.45 (m,2H); 3.15 (m, 2H).

PREPARATIVE EXAMPLE 4

[0096]

[0097] Combine 15 g (38.5 mmol) of4-(8-chloro-3-bromo-5.6-dihydro-11H-benzo[5,6]cyclohepta[1,2-b]pyridin-1-ylidene)-1-piperidine-1-carboxylicacid ethyl ester and 150 mL of concentrated H₂SO₄ at −5° C., then add3.89 g (38.5 mmol) of KNO₃ and stir for 4 hours. Pour the mixture into 3L of ice and basify with 50% NaOH (aqueous). Extract with CH₂Cl₂, dryover MgSO₄, then filter and concentrate in vacuo to a residue.Recrystallize the residue from acetone to give 6.69 g of the product. ¹HNMR (CDCl₃, 200 MHz); 8.5 (s, 1H); 7.75 (s, 1H); 7.6 (s, 1H); 7.35 (s,1H); 4.15 (q, 2H); 3.8 (m, 2H); 3.5-3.1 (m, 4H); 3.0-2.8 (m, 2H);2.6-2.2 (m, 4H); 1.25 (t, 3H).

[0098] Combine 6.69 g (13.1 mmol) of the product of Step A and 100 mL of85% EtOH/water, then add 0.66 g (5.9 mmol) of CaCl₂ and 6.56 g (117.9mmol) of Fe and heat the mixture at reflux overnight. Filter the hotreaction mixture through celite® and rinse the filter cake with hotEtOH. Concentrate the filtrate in vacuo to give 7.72 g of the product.Mass Spec.: MH⁺=478.0

[0099] Combine 7.70 g of the product of Step B and 35 mL of HOAc, thenadd 45 mL of a solution of Br₂ in HOAc and stir the mixture at roomtemperature overnight. Add 300 mL of 1 N NaOH (aqueous), then 75 mL of50% NaOH (aqueous) and extract with EtOAc. Dry the extract over MgSO₄and concentrate in vacuo to a residue. Chromatograph the residue (silicagel, 20%-30% EtOAc/hexane) to give 3.47 g of the product (along withanother 1.28 g of partially purified product). Mass Spec.: MH⁺=555.9. ¹HNMR (CDCl₃, 300 MHz); 8.5 (s. 1H); 7.5 (s, 1H); 7.15 (s, 1H); 4.5 (s,2H); 4.15 (m. 3H); 3.8 (br s. 2H); 3.4-3.1 (m, 4H); 9-2.75 (m, 1H);2.7-2.5 (m, 2H); 2.4-2.2 (m. 2H); 1.25 (m, 3H).

[0100] Combine 0.557 g (5.4 mmol) of t-butylnitrite and 3 mL of DMF, andheat the mixture at to 60-70° C. Slowly add (dropwise) a mixture of 2.00g (3.6 mmol) of the product of Step C and 4 mL of DMF, then cool themixture to room temperature. Add another 0.64 mL of t-butylnitrite at40° C. and reheat the mixture to 60-70° C. for 0.5 hrs. Cool to roomtemperature and pour the mixture into 150 mL of water. Extract withCH₂Cl₂, dry the extract over MgSO₄ and concentrate in vacuo to aresidue. Chromatograph the residue (silica gel, 10%-20% EtOAc/hexane) togive 0.74 g of the product. Mass Spec.: MH⁺=541.0.

[0101]¹H NMR (CDCl3, 200 MHz); 8.52 (s, 1H); 7.5 (d, 2H); 7.2 (s, 1H);4.15 (q, 2H); 3.9-3.7 (m, 2H); 3.5-3.1 (m. 4H); 3.0-2.5 (m, 2H); 2.4-2.2(m, 2H); 2.1-1.9.(m, 2H); 1.26 (t, 3H).

[0102] Combine 0.70 g (1.4 mmol) of the product of Step D and 8 mL ofconcentrated HCl (aqueous) and heat the mixture at reflux overnight. Add30 mL of 1 N NaOH (aqueous), then 5 mL of 50% NaOH (aqueous) and extractwith CH₂Cl₂. Dry the extract over MgSO₄ and concentrate in vacuo to give0.59 g of the title compound. Mass Spec.: M⁺=468.7. m.p.=123.9°-124.2°C.

[0103] The title compound can be cleaved by the methodology ofPreparative Example 3 to prepare the corresponding 11-ketone having3,10-dibromo-8-chloro substituents.

PREPARATIVE EXAMPLE 5

[0104]

[0105] Combine 40.0 g (0.124 mole) of the starting ketone and 200 mL ofH₂SO₄ and cool to 0° C. Slowly add 13.78 g (0.136 mole) of KNO₃ over aperiod of 1.5 hrs., then warm to room temperature and stir overnight.Work up the reaction using substantially the same procedure as describedfor Preparative Example 2, Step A. Chromatograph (silica gel, 20%, 30%,40%, 50% EtOAc/hexane, then 100% EtOAc) to give 28 g of the 9-nitroproduct, along with a smaller quantity of the 7-nitro product and 19 gof a mixture of the 7-nitro and 9-nitro compounds.

[0106] React 28 g (76.2 mmol) of the 9-nitro product of Step A, 400 mLof 85% EtOH/water, 3.8 g (34.3 mmol) of CaCl₂ and 38.28 g (0.685 mole)of Fe using substantially the same procedure as described forPreparative Example 2, Step C, to give 24 g of the product

[0107] Combine 13 g (38.5 mmol) of the product of Step B, 140 mL of HOAcand slowly add a solution of 2.95 mL (57.8 mmol) of Br₂ in 10 mL of HOAcover a period of 20 min. Stir the reaction mixture at room temperature,then concentrate in vacuo to a residue. Add CH₂Cl₂ and water, thenadjust to pH=8-9 with 50% NaOH (aqueous). Wash the organic phase withwater, then brine and dry over Na₂SO₄. Concentrate in vacuo to give 11.3g of the product.

[0108] Cool 100 mL of concentrated HCl (aqueous) to 0° C., then add 5.61g (81.4 mmol) of NaNO₂ and stir for 10 min. Slowly add (in portions)11.3 g (27.1 mmol) of the product of Step C and stir the mixture at0°-3° C. for 2.25 hrs. Slowly add (dropwise) 180 mL of 50% H₃PO₂(aqueous) and allow the mixture to stand at 0° C. overnight. Slowly add(dropwise) 150 mL of 50% NaOH over 30 min., to adjust to pH=9, thenextract with CH₂Cl₂. Wash the extract with water, then brine and dryover Na₂SO₄. Concentrate in vacuo to a residue and chromatograph (silicagel, 2% EtOAc/CH₂Cl₂) to give 8.6 g of the product.

EXAMPLE 1

[0109]

[0110] The compound from Preparative Example 1 (0.95 gm, 1.9mmol) wasdissolved in 34 ml of toluene. Triethylamine (1 ml) andethylchloroformate (1.82 ml, 10 eq.) were added and the reaction mixturerefluxed for two hours. The reaction mixture was cooled to ambienttemperature and evaporated to an oil. The oil was chromatographed onsilica gel using 15 to 20% ethylacetate/hexanes to obtain 0.77 gm ofethyl4-(3,10-dibromo-8-chloro-6,11-dihydro-11-hydroxy-5H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-yl)-1-piperidinecarboxylate.FABMS (M+H)=559

[0111] The compound from Preparative Example 2 (0.37 gm) was dissolvedin 5 ml of concentrated hydrochloric acid and refluxed for 18 hours. Themixture was evaporated to a brown solid of the compound4-(3,10-dibromo-8-chloro-6.11-dihydro-11-hydroxy-5H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-yl)-1-piperidineand used without chromatography.

[0112] The compound of Preparative Example 3 (100 mg, 0.206 mmol) wasdissolved in 2 ml of N,N-dimethylformamide. 4-Pyridylacetic acid-N-oxide(126mg, 0.82mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimidehydrochloride (DEC) (0.079 mg, 0.5 mmol)), 1-hydroxybenzotriazole (HOBt)(0.056 gm, 0.5 mmol), and N-methylmorpholine (0.23 ml, 2.0 mmol) wereadded and the reaction mixture stirred at ambient temperature. After 24hours, the reaction mixture was added to brine and extracted with 3×15ml of ethylacetate. The combined ethylacetate washes were combined andthe solvent evaporated under vacuo to give a gum. The gum waschromatographed flash silica gel using 10% methanol/methylenechloride asthe eluent to obtain 0.076 gm of4-(3,10-dibromo-8-chloro-6,11-dihydro-11-hydroxy-5H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-yl)-1-(4-pyridinylacetyl)piperidineN1-oxide. FABMS (M+H)=622

EXAMPLE 2

[0113]

[0114] The procedure of Example 1 above was followed replacing4-pyridylacetic acid-N-oxide with N-Boc-4-piperadineacetic acid toobtain4-(3,10-dibromo-8-chloro-6,11-dihydro-11-hydroxy-5H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-yl)-1-(N-BOC-4-piperdinylacetyl)piperidinein 85% yield. High resolution MS: observed=712.0975

[0115] The compound of Step A above (0.21 gm) was dissolved in 50%trifluoroacetic acid/methylenechloride and stirred for 1 hour. Thereaction mixture was evaporated to obtain an oil which was dissolved in2 ml of methylenechloride to provide4-[2-[4-(3,10-dibromo-8-chloro-6,11-dihydro-11-hydroxy-5H-benzo[5,6]-cyclohepta[1,2-b]pyridin-11-yl)-1-piperdinyl]-2-oxoethyl]-1-piperidine.

[0116] Trimethylsilylisocyanate (234 ul. 1.47 mmol) was added and thereaction mixture stirred at ambient temperature for 15 hours. Thesolvent was evaporated and the crude product chromatographed on silicagel using 7.5% methanol/methylenechloride to obtain 100 mg, 62%, of4-[2-[4-(3,10-dibromo-8-chloro-6,1-dihydro-11-hydroxy-5H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-yl)-1-piperdinyl]-2-oxoethyl]-1-piperidinecarboxamide.High resolution MS: observed=655.0509

EXAMPLE 3

[0117]

[0118] The compound of Example 2 Step A above (0.069 g, 0.113 mmol) wasdissolved in 2 ml of N,N-dimethylformamide. Sodium carbonate (0.036 g,0.34 mmol) and bromoacetamide (0.023 g, 0.17 mmol) were added and thereaction mixture stirred at ambient temperature for 24 hours. Themixture was added to brine and extracted with ethylacetate. Theethylacetate layer was dried over magnesium sulfate, filtered andevaporated to obtain a crude solid. The crude solid was chromatographedon silica gel using 5% methanol/methylenechloride to obtain4-[2-[4-(3,10-dibromo-8-chloro-6,11-dihydro-11-hydroxy-5H-benzo[5,6]cyclohepta-[1,2-B]pyridin-11-yl)-1-piperidinyl]-2-oxoethyl]-1-piperidineacetamide.High resolution MS: observed=669.0666

[0119] The following compounds can be prepared utilizing the procedureof Example 1 above and substituting the following carboxylic acids for4-pyridylacetic acid-N-oxide. Carboxylic Acid T = in Formula 1.0HOOCCH₂CONH₂ —OCCH₂CONH₂

HOOCCH₂CO₂H —OCCH₂CO₂H

HOOCCH₂NH₂ —OCCH₂NH₂

HOOCCH₂—COOH —OCCH₂—COOH

[0120] Assays

[0121] FPT IC₅₀ (inhibition of farnesyl protein transferase, in vitroenzyme assay) and COS Cell IC₅₀ (Cell-Based Assay) severe determinedfollowing the assay procedures described in WO 95/10516, published Apr.20, 1995. GGPT IC₅₀ (inhibition of geranylgeranyl protein transferase,in vitro enzyme assay), Cell Mat Assay, and anti-tumor activity (in vivoanti-tumor studies) could be determined by the assay proceduresdescribed in WO 95/10516. The disclosure of WO 95/10516 is incorporatedherein by reference thereto.

[0122] Additional assays can be carried out by following essentially thesame procedure as described above, but with substitution of alternativeindicator tumor cell lines in place of the T24-BAG cells. The assays canbe conducted using either DLD-1-BAG human colon carcinoma cellsexpressing an activated K-ras gene or SW620-BAG human colon carcinomacells expressing an activated K-ras gene. Using other tumor cell linesknown in the art, the activity of the compounds of this inventionagainst other types of cancer cells could be demonstrated.

[0123] Soft Agar Assay:

[0124] Anchorage-independent growth is a characteristic of tumorigeniccell lines. Human tumor cells are suspended in growth medium containing0.3% agarose and an indicated concentration of a farnesyl transferaseinhibitor. The solution is overlayed onto growth medium solidified with0.6% agarose containing the same concentration of farnesyl transferaseinhibitor as the top layer. After the top layer is solidified, platesare incubated for 10-16 days at 37° C. under 5% CO₂ to allow colonyoutgrowth. After incubation, the colonies are stained by overlaying theagar with a solution of MTT(3-[4.5-dimethyl-thiazol-2-yl]-2,5-diphenyltetrazolium bromide,Thiazolyl blue) (1 mg/mL in PBS). Colonies can be counted and the IC₅₀'scan be determined.

[0125] Results from the in vitro enzyme assay are given in Table 1.TABLE 1 FPT IC50 Example No. Compound (μM) #1 Step C

<0.002 #2 Step C

0.0108 #2 Step A

0.042 #3

0.0087 #2 Step B

0.0125

[0126] For preparing pharmaceutical compositions from the compoundsdescribed by this invention, inert, pharmaceutically acceptable carrierscan be either solid or liquid. Solid form preparations include powders,tablets, dispersible granules, capsules, cachets and suppositories. Thepowders and tablets may be comprised of from about 5 to about 70 percentactive ingredient. Suitable solid carriers are known in the art, e.g.magnesium carbonate, magnesium stearate, talc, sugar, lactose. Tablets,powders, cachets and capsules can be used as solid dosage forms suitablefor oral administration.

[0127] For preparing suppositories, a low melting wax such as a mixtureof fatty acid glycerides or cocoa butter is first melted, and the activeingredient is dispersed homogeneously therein as by stirring. The moltenhomogeneous mixture is then poured into convenient sized molds, allowedto cool and thereby solidify.

[0128] Liquid form preparations include solutions, suspensions andemulsions. As an example may be mentioned water or water-propyleneglycol solutions for parenteral injection.

[0129] Liquid form preparations may also include solutions forintranasal administration.

[0130] Aerosol preparations suitable for inhalation may includesolutions and solids in powder form, which may be in combination with apharmaceutically acceptable carrier, such as an inert compressed gas.

[0131] Also included are solid form preparations which are intended tobe converted, shortly before use, to liquid form preparations for eitheroral or parenteral administration. Such liquid forms include solutions,suspensions and emulsions.

[0132] The compounds of the invention may also be deliverabletransdermally. The transdermal compositions can take the form of creams,lotions, aerosols and/or emulsions and can be included in a transdermalpatch of the matrix or reservoir type as are conventional in the art forthis purpose.

[0133] Preferably the compound is administered orally.

[0134] Preferably, the pharmaceutical preparation is in unit dosageform. In such form the preparation is subdivided into unit dosescontaining appropriate quantities of the active component, e.g., aneffective amount to achieve the desired purpose.

[0135] The quantity of active compound in a unit dose of preparation maybe varied or adjusted from about 0.1 mg to 1000 mg, more preferably fromabout 1 mg. to 300 mg. according to the particular application.

[0136] The actual dosage employed may be varied depending upon therequirements of the patient and the severity of the condition beingtreated. Determination of the proper dosage for a particular situationis within the skill of the art. Generally, treatment is initiated withsmaller dosages which are less than the optimum dose of the compound.Thereafter, the dosage is increased by small increments until theoptimum effect under the circumstances is reached. For convenience, thetotal daily dosage may be divided and administered in portions duringthe day if desired.

[0137] The amount and frequency of administration of the compounds ofthe invention and the pharmaceutically acceptable salts thereof will beregulated according to the judgment of the attending clinicianconsidering such factors as age, condition and size of the patient aswell as severity of the symptoms being treated. A typical recommendeddosage regimen is oral administration of from 10 mg to 2000 mg/daypreferably 10 to 1000 mg/day, in two to four divided doses to blocktumor growth. The compounds are non-toxic when administered within thisdosage range.

[0138] The following are examples of pharmaceutical dosage forms whichcontain a compound of the invention. The scope of the invention in itspharmaceutical composition aspect is not to be limited by the examplesprovided.

PHARMACEUTICAL DOSAGE FORM EXAMPLES Example A

[0139] Tablets No. Ingredients mg/tablet mg/tablet 1. Active compound100 500 2. Lactose USP 122 113 3. Corn Starch, Food Grade 30 40 as a 10%paste in Purified Water 4. Corn Starch, Food Grade 45 40 5. MagnesiumStearate 3 7 Total 300 700

Method of Manufacture

[0140] Mix Item Nos. 1 and 2 in a suitable mixer for 10-15 minutes.Granulate the mixture with Item No. 3. Mill the damp granules through acoarse screen (e.g., ¼″, 0.63 cm) if necessary. Dry the damp granules.Screen the dried granules if necessary and mix with Item No. 4 and mixfor 10-15 minutes. Add Item No. 5 and mix for 1-3 minutes. Compress themixture to appropriate size and weigh on a suitable tablet machine.

Example B

[0141] Capsules No. Ingredient mg/capsule mg/capsule 1. Active compound100 500 2. Lactose USP 106 123 3. Corn Starch, Food Grade 40 70 4.Magnesium Stearate NF 7 7 Total 253 700

[0142] Method of Manufacture

[0143] Mix Item Nos. 1, 2 and 3 in a suitable blender for 10-15 minutes.Add Item No. 4 and mix for 1-3 minutes. Fill the mixture into suitabletwo-piece hard gelatin capsules on a suitable encapsulating machine.

[0144] While the present invention has been described in conjunctionwith the specific embodiments set forth above, many alternatives,modifications and variations thereof will be apparent to those ofordinary skill in the art. All such alternatives, modifications andvariations are intended to fall Within the spirit and scope of thepresent invention.

What is claimed is:
 1. A compound of the formula:

or a pharmaceutically acceptable salt or solvate thereof, wherein: a represents N or NO⁻; R¹ and R³ are the same or different and each represents halo; R² and R⁴ are the same or different and each is selected from H and halo, provided that at least one of R² and R⁴ is H; T is a substituent selected from SO₂R or

Z is O or S; n is zero or an integer from 1 to 6; R is alkyl aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl, heterocycloalkyl, or N(R⁵)₂; R⁵ is H, alkyl, aryl, heteroaryl or cycloalkyl.
 2. The compound of claim 1 having the formula:

wherein a, T, R¹ and R³ are as defined in claim
 1. 3. The compound of claim 1 having the formula:

wherein a, T, R¹, R³ and R⁴ are as defined in claim
 1. 4. The compound of claim 1 having the formula:

wherein a, T, R¹, R² and R⁴ are as defined in claim
 1. 5. The compound of claim 1 having the formula:

wherein a, T, R¹, R², R³ and R⁴ are as defined in claim
 1. 6. The compound of claim 1 having the formula:

wherein a, T, R¹, R², R³ and R⁴ are as defined in claim
 1. 7. The compound of claim 2, wherein R¹ is bromo and R³ is chloro.
 8. The compound of claim 3, wherein R¹ is bromo, R³ is chloro and R⁴ is bromo.
 9. The compound of claim 4, wherein R¹ is bromo, R² is bromo and R³ is chloro.
 10. The compound of claim 7, wherein T is —SO₂methyl or a group

wherein R is a 3-pyridinyl N-oxide, 4-pyridinyl N-oxide, 4-piperdinyl, 3-piperdinyl or 3-pyrrolidinyl group, wherein: the 4-piperdinyl, 3-piperdinyl or 3-pyrrolidinyl groups may be substituted on the piperindinyl or pyrrolidinyl nitrogen with a group R⁹; R⁹ is selected from —C(O)N(R¹⁰)₂, —CH₂C(O)N(R¹⁰)₂, —SO₂R¹⁰, —SO₂N(R¹⁰)₂, —C(O)R¹¹, —C(O)OR¹¹, alkyl, aryl, aralkyl, cycloalkyl, heterocycloalkyl or heteroaryl; each R¹⁰ independently represents H, alkyl, aryl, or aralkyl; and R¹¹ is alkyl, aryl, aralkyl, heteroaryl or heterocycloalkyl.
 11. The compound of claim 8, wherein T is —SO₂methyl or a group

wherein R is a 3-pyridinyl N-oxide, 4-pyridinyl N-oxide. 4-piperdinyl, 3-piperdinyl or 3-pyrrolidinyl group, wherein: the 4-piperdinyl, 3-piperdinyl or 3-pyrrolidinyl groups may be substituted on the piperindinyl or pyrrolidinyl nitrogen with a group R⁹; R⁹ is selected from —C(O)N(R¹⁰)₂, —CH₂C(O)N(R¹⁰)₂, —SO₂R¹⁰, —SO₂N(R¹⁰)₂, —C(O)R¹¹, —C(O)OR¹¹, alky, aryl, aralkyl, cycloalkyl, heterocycloalkyl or heteroaryl; each R¹⁰ independently represents H, alkyl, aryl, or aralkyl; and R¹¹ is alkyl, aryl, aralkyl, heteroaryl or heterocycloalkyl.
 12. The compound of claim 9, wherein T is —SO₂methyl or a group

wherein R is a 3-pyridinyl N-oxide, 4-pyridinyl N-oxide, 4-piperdinyl, 3-piperdinyl or 3-pyrrolidinyl group, wherein: the 4-piperdinyl, 3-piperdinyl or 3-pyrrolidinyl groups may be substituted on the piperindinyl or pyrrolidinyl nitrogen With a group R⁹; R⁹ is selected from —C(O)N(R¹⁰)₂, —CH₂C(O)N(R¹⁰)₂, —SO₂R¹⁰, —SO₂N(R¹⁰)₂, —C(O)R¹¹, —C(O)OR¹¹, alkyl, aryl, aralkyl, cycloalkyl, heterocycloalkyl or heteroaryl; each R¹⁰ independently represents H, alkyl, aryl, or aralkyl; and R¹¹ is alkyl, aryl, aralkyl, heteroaryl or heterocycloalkyl.
 13. The compound of claim 10, wherein the carbon in the C-11 position is in the R-configuration.
 14. The compound of claim 11, wherein the carbon in the C-11 position is in the R-configuration.
 15. The compound of claim 12, wherein the carbon in the C-11 position is in the R-configuration.
 16. The compound of claim 10, wherein the carbon in the C-11 position is in the S-configuration.
 17. The compound of claim 11, wherein the carbon in the C-11 position is in the S-configuration.
 18. The compound of claim 12, wherein the carbon in the C-11 position is in the S-configuration.
 19. A compound of claim 1 having the formula:


20. A method of treating tumor cells expressing an activated ras oncogene comprising administering an effective amount of a compound of claim
 1. 21. The method of claim 20 Wherein tumor cells treated are pancreatic tumor cells, lung cancer cells, myeloid leukemia tumor cells, thyroid follicular tumor cells, myelodysplastic tumor cells, epidermal carcinoma tumor cells, bladder carcinoma tumor cells, colon tumors cells, breast tumor cells and prostate tumor cells.
 22. A method of treating tumor cells wherein the Ras protein is activated as a result of oncogenic mutation in genes other than the Ras gene, comprising administering an effective amount of a compound of claim
 1. 23. A method of inhibiting farnesyl protein transferase comprising the administration of an effective amount of the compound of claim
 1. 24. A pharmaceutical composition for inhibiting farnesyl protein transferase comprising an effective amount of compound of claim 1 in combination with a pharmaceutically acceptable carrier. 